rs1800562 represents a SNP that accounts for ~85% of all cases of hemochromatosis, a disorder whose symptoms include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. OMIM indicates that liver cancer is responsible for about one-third of deaths of rs1800562(A;A) homozygotes, and since hemochromatosis is a relatively easily treated disorder if diagnosed, this is a form of preventable cancer.
The rs1800562(A) allele is known as the C282Y mutation, and it is found at a frequency of around 5-10% in many Caucasian populations, leading to an incidence of (A;A) homozygotes around 1 in 200. Early identification of rs1800562(A;A) homozygotes can prevent complications of hemochromatosis; however, the percentage of all (A;A) homozygotes who actually develop clinical signs of hemochromatosis may be relatively low, may depend on sex (see below), and appears to be influenced by other SNPs yet to all be discovered as well as (unidentified) environmental factors, possibly including the amount of iron in the diet.
In rs1800562(A;A) patients who do develop hemochromatosis, a SNP has been identified which increases the risk of cardiomyopathy (a form of heart disease). rs4880(T;T) homozygotes are at ~10 fold increased risk for dilated- or non-dilated cardiopathy based on a study of 217 patients.[PMID 15591282]
rs235756, a SNP in the BMP2 gene, is another SNP that may influence the development of hemochromatosis in rs1800562(A;A) individuals, at least if serum transferrin levels are a good indication. Transferrin levels increased with increasing copies of the rs235756(T) allele.[PMID 17847004]
So which rs1800562(A;A) individuals actually develop clinical signs of hemochromatosis? In a recent study of ~200 rs1800562(A;A) homozygotes, ~30% of the males had iron-overload related diseases versus 1% of the females. Male C282Y homozygotes with a serum ferritin level of 1,000 mcg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who lacked a rs1800562(A) allele.[PMID 18199861]
Women who are rs1800562(A) homozygotes are less affected by hemochromatosis due to elimination of excess iron during menstruation, but may become affected after menopause.
According to Coriell, in Caucasian populations:
- (A;A) - 0.4% of individuals, carrying 2 copies of the risk variant (33-57% of such males will have quite elevated iron levels; 3-16% if female)
- (G;A) - 12% carry 1 copy of the risk variant and 1 copy of the non-risk variant
- (G;G) - 87.6% carry (only) the non-risk variant
|Trait||Serum markers of iron status|
|Title||Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels|
|Odds Ratio||NR NR|
|Title||A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium|
|Odds Ratio||1.41 [1.13-1.69] fl increase|
|Trait||Serum markers of iron status|
|Title||Common variants in TMPRSS6 are associated with iron status and erythrocyte volume|
|Odds Ratio||0.20 [0.12-0.28] SD increase|
|Title||Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium|
|Odds Ratio||0.31 [0.21-0.41] % increase|
[PMID 20029940] Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease
[PMID 20858683] Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways
|Title||A genome-wide association study of red blood cell traits using the electronic medical record|
|Odds Ratio||0.49 [0.33-0.65] unit increase|
|Title||Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.|
|Odds Ratio||0.6290 [0.53-0.73] unit decrease|
|Title||Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.|
|Odds Ratio||0.3890 [0.24-0.54] ng/ml increase|
|Title||Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.|
|Odds Ratio||0.1770 [0.13-0.23] mg/l increase|
|Title||Biological, clinical and population relevance of 95 loci for blood lipids.|
|Odds Ratio||2.2200 None|
|Disease||Hereditary hemochromatosis, Transferrin serum level quantitative trait locus 2, Microvascular complications of diabetes 7|
|CLNDBN||Hereditary hemochromatosis, Transferrin serum level quantitative trait locus 2, Microvascular complications of diabetes 7|
|CLNSRC||OMIM Allelic Variant|
[PMID 18603647] Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.
[PMID 18795173] Variants in iron metabolism genes predict higher blood lead levels in young children.
[PMID 19165391] Iron metabolism genes, low-level lead exposure, and QT interval.
[PMID 19401444] Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism.
[PMID 19474294] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.
[PMID 19673882] A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.
[PMID 20659343] HFE gene variants modify the association between maternal lead burden and infant birthweight: a prospective birth cohort study in Mexico City, Mexico.
[PMID 21240526] Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review.
[PMID 21679129] Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high-resolution melting with the Rotor-Gene 6000(R) instrument.
[PMID 22611049] Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations.
[PMID 18246059] Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? Conclusion: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.
|qualified_impact||Low clinical importance, pathogenic|
|summary||This variant is associated with hereditary haemochromatosis, 80% of patients with that disease are homozygous for this variant. However, the penetrance is low, in Beutler et al. they note that only 1 of their 158 homozygotes met criteria for diagnosis with the condition.|
[PMID 23389292] Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
|Title||GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children.|
|Odds Ratio||.19 [0.11-0.27] unit increase|